Many quinoxaline-1,4-dioxides administered to animals are effective in the control of urinary tract and systemic infections, chronic respiratory disease in poultry and infectious sinusitis in turkeys such as disclosed in U.S. Pat. No. 3,371,090. Of special interest is their use in the control of swine dysentery. These anti-bacterial agents are useful in both prophylaxis and therapy. By controlling or eliminating many common bacterial infections which afflict animals, these agents also function as both growth and feed efficiency promotors. Quinoxaline-1,4-dioxide anti-bacterial agents have the structure ##STR1## wherein each of R.sub.1 and R.sub.2 is individually selected from the group consisting of hydrogen and lower alkyl; R.sub.3 is selected from the group consisting of
NH--CO--NH.sub.2 PA1 NH--CS--NH.sub.2 PA1 NH--C(NH)--NH.sub.2 PA1 NHR.sub.4 PA1 NHCOOR.sub.5 PA1 NHCOR.sub.6 PA1 OR.sub.7 ##STR2## wherein
R.sub.4 is selected from the group consisting of lower alkyl, phenyl, benzyl and hydroxyalkyl containing from 2 to 4 carbon atoms;
R.sub.5 is selected from the group consisting of lower alkyl, hydroxyalkyl containing from 2 to 4 carbon atoms, and haloalkyl containing from 2 to 4 carbon atoms;
R.sub.6 is selected from the group consisting of lower alkyl and phenyl; and
R.sub.7 is selected from the group consisting of hydrogen and lower alkyl. The term "lower alkyl" as used herein includes the branched-chain as well as the straight-chain radicals of those lower alkyl group having three or more carbon atoms. Particularly preferred as an anti-bacterial is 2-formyl-quinoxaline-1,4-dioxide carbomethoxy-hydrozone known by the common name of carbadox.
Carbadox is being supplied to the consumer as premix which is further blended with an aminal feed to produce an ultimate product containing a pharmaceutically effective concentration of carbadox. The composition of the premix varies depending upon the area of the world in which it is intended for consumption. The carrier is also varied with an effort made to use a material, usually farinaceous, which is readily available in the area in which it is to be consumed. Typical carbadox premixes contain about 85 to 98 percent carrier and anywhere from 2 to 12 percent carbadox. Up to about 1% by weight of silicon dioxide or 10% by weight of calcium carbonate may be used in addition to farinaceous materials. Also an effective amount of calcium propionate as a preservative, usually about 0.2% by weight, is sometimes added. Among the fairinaceous carriers are rice bran, corn germ meal, soybean meal, soybean grits, wheat middlings, corn gluten feed, soft phosphate rock, cornmeal, rapeseed meal and soybean mill run.
Because of the physical nature of the carbadox crystal, a nature it shares with other quinoxaline-1,4-dioxides, difficulties are encountered in the formulation of a dustfree premix containing a uniform amount of carbadox. Present processes to produce carbadox yield an extremely fine crystalline material with typically about 3% by weight smaller in size than 5 micrometers, 23 percent between 5 and 10 micrometers and 74 percent larger than 10 micrometers. This particle size distribution can, however be extremely deceiving since the carbadox crystal is very friable and tends with abrasion to be reduced greatly in size.
Because of the small particle size of carbadox relative to the carrier, any dust escaping from the blender in which the premix is formulated would be expected to be composed mostly of carbadox. Measurements have in fact shown that said escaped dust is about 93 percent carbadox. Though particles smaller than 10 micrometers are usually regarded as respirable, this presents no problem in the current application because all mixing is done in closed systems with dust collectors. Nevertheless, the escaping dust does create difficulty in producing a uniform formulation. The carbadox which is trapped in a dust collector, which in most instances is a bag house, is recycled back to the mixer. However 6 or 7 batches may be run before the collected material is removed, weighed, and recycled. As a result the initial mixtures will tend to be low in carbadox composition and the batch containing the recycled material high in carbadox concentration. Uniformity of composition requires, therefore, that even in a closed system the amount of dust generated in blending process be an absolute minimum.
The premix remains dusty even after it is removed from the blender and packaged for shipment. It is believed that some carbadox may actually be lost in shipment and it is known that some is definitely lost when the premix is formulated into a feed by the ultimate user. Again, uniformity of composition requires a stable, that is, dustless blend of carbadox and carrier. Furthermore, it is generally undesirable to market a product which contains or generates respirable dust even though no medical hazard may be immediately apparent.
Dustless quinoxaline-1,4-dioxide premixes are also extremely desirable because of their safety. The tendency of carbadox to explode is great. Its minimum ignition energy is extremely low and the crystal is highly flammable and self-sustaining in the absence of air. In stable, dustless premixes these dangers are not encountered. However, a hazard does exist whenever carbadox separates from its carrier. Stable premixes eliminate the possibility of baghouse fires and explosions in transit. Dusty premixes may not be shipped by air freight whereas the product of the current invention is sufficiently safe to be shipped by any mode of transportation.